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Pathophysiological Consequences (pathophysiological + consequence)
Selected AbstractsFree fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and ,-cell dysfunctionEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2002G. Boden Abstract Plasma free fatty acids (FFA) play important physiological roles in skeletal muscle, heart, liver and pancreas. However, chronically elevated plasma FFA appear to have pathophysiological consequences. Elevated FFA concentrations are linked with the onset of peripheral and hepatic insulin resistance and, while the precise action in the liver remains unclear, a model to explain the role of raised FFA in the development of skeletal muscle insulin resistance has recently been put forward. Over 30 years ago, Randle proposed that FFA compete with glucose as the major energy substrate in cardiac muscle, leading to decreased glucose oxidation when FFA are elevated. Recent data indicate that high plasma FFA also have a significant role in contributing to insulin resistance. Elevated FFA and intracellular lipid appear to inhibit insulin signalling, leading to a reduction in insulin-stimulated muscle glucose transport that may be mediated by a decrease in GLUT-4 translocation. The resulting suppression of muscle glucose transport leads to reduced muscle glycogen synthesis and glycolysis. In the liver, elevated FFA may contribute to hyperglycaemia by antagonizing the effects of insulin on endogenous glucose production. FFA also affect insulin secretion, although the nature of this relationship remains a subject for debate. Finally, evidence is discussed that FFA represent a crucial link between insulin resistance and ,-cell dysfunction and, as such, a reduction in elevated plasma FFA should be an important therapeutic target in obesity and type 2 diabetes. [source] Inhibition of adiponectin production by homocysteine: A potential mechanism for alcoholic liver disease,HEPATOLOGY, Issue 3 2008Zhenyuan Song Although recent evidence suggests that down-regulation of production of the adipocyte hormone adiponectin has pathophysiological consequences for the development of alcoholic liver disease (ALD), the underlying mechanisms are elusive. Abnormal hepatic methionine-homocysteine metabolism induced by prolonged alcohol exposure has been reported both in clinical and experimental studies of ALD. Here, we conducted both in vivo and in vitro experiments to examine the effects of prolonged alcohol exposure on homocysteine levels in adipose tissue, its potential involvement in regulating adiponectin production, and the consequences for ALD. Chronic alcohol exposure decreased the circulating adiponectin concentration and adiponectin messenger RNA (mRNA) and protein levels in epididymal fat pads. Alcohol feeding induced modest hyperhomocysteinemia and increased homocysteine levels in the epididymal fat pad, which was associated with decreased mRNA levels of cystationine ,-synthase. Betaine supplementation (1.5%, wt/vol) in the alcohol-fed mice reduced homocysteine accumulation in adipose tissue and improved adiponectin levels. Moreover, exogenous homocysteine administration reduced gene expression, protein levels, and secretion of adiponectin in primary adipocytes. Furthermore, rats fed a high-methionine diet (2%, wt/wt) were hyperhomocysteinemic and had decreased adiponectin levels in both plasma and adipose tissue, which was associated with suppressed AMP-activated protein kinase activation in the liver. Mechanistic studies revealed that both inactivation of the extracellular signal regulated kinase 1/2 pathway and induction of endoplasmic reticulum stress response, specifically C/EBP homologous protein expression, may contribute to the inhibitory effect exerted by homocysteine. Conclusion: Chronic alcohol feeding caused abnormal accumulation of homocysteine in adipocytes, which contributes to decreased adiponectin production in ALD. (HEPATOLOGY 2008.) [source] Influence of a standardized closed soft tissue trauma on resistance to local infection.JOURNAL OF ORTHOPAEDIC RESEARCH, Issue 2 2003An experimental study in rats Abstract Purpose: The etiology of local posttraumatic infection in the locomotor system depends on the amount, virulence and pathogenicity of the inoculated microorganisms and the local/systemic host damage due to the type and extent of the accident or iatrogenic trauma. The relative effect of these factors remains unclear. In particular, it is still unclear today whether,in presence of microorganisms,soft tissue damage and its pathophysiological consequences lead to infection after soft tissue trauma, or whether the bacterial contamination is the primarily cause for posttraumatic infection. The aim of the project was to gain information on the consequences of a soft tissue injury in terms of resistance to local infection. Since clinical populations are too heterogeneous, the problem was investigated in a standardized, reduced (no surgery or implants) experimental in vivo model. Method: In female Sprague-Dawley-rats with a standardized closed soft tissue trauma to the tibialis anterior muscle (group I: n = 13) or without (group II: n = 13), we compared the incidence of local infection after a pairwise local, percutaneously injected bacterial challenge with various concentrations of Staphylococcus aureus (2 × 104 -2 × 106 colony forming units, CFU). The standardized closed soft tissue trauma was created by application of a specially designed, computer controlled impact device. The contaminated soft tissue and the underlying bone were removed under sterile conditions after five days and quantitatively evaluated for bacterial growths. Infection was defined as positive bacterial growth at the soft tissue and/or bone. A stepwise experimental design with an ,up-and-down" dosage technique was used to adjust the bacterial challenge in the area of the ID50 (50% infection dose). Statistical evaluation of the difference between the infection rates of both groups was performed by two-sided fisher exact test (p<0.05). Results: The overall infection rate was 46%. For the group with soft tissue trauma the ID50 was 1.32 × 105 CFU and 1.05 × 106 CFU for the group without soft tissue trauma. The infection rate was 69% (9 of 13 animals) for the group with soft tissue trauma and 23% (3 of 13 animals) for the group without soft tissue trauma. This difference is statistically significant (p = 0.047). Conclusions: The infection rate after a standardized closed soft tissue injury was significantly higher and the ID50 lower than without soft tissue trauma. Our results demonstrate that in presence of microorganisms it is not primarily the bacterial contamination but rather the soft tissue damage and its pathophysiological consequences resulting in decreased infection resistance that secondarily lead to infection. © 2002 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved. [source] 2433: A revolutionary hypothesis to explain Marx's line and progressive disease at the lid marginACTA OPHTHALMOLOGICA, Issue 2010AJ BRON Purpose The conjunctiva of the lid margin is protected from direct exposure to the atmosphere, by the tear meniscus. We examine the pathophysiological consequences of evaporation from this compartment. Methods A consideration of empirical data. Results The concave meniscus thins progressively to the point where it is pinned at the mucocutaneous junction (MCJ). We predict that, as a result, over the interblink period, evaporation generates a solute gradient which peaks behind the MCJ and is amplified over multiple cycles of the blink. We hypothesise that this creates a hyperosmolar state here which: i. stresses epithelial cells behind the MCJ, ii. stimulates a high cell turnover and iii. leads to immaturity of the surface cells and their glycocalyx. This is considered to explain an increased permeability to dyes at this site (rose bengal, lissamine green and fluorescein) and the stainability with dyes which is termed Marx's line. This gradient mechanism could also concentrate proteins, such as inflammatory mediators, at this location. Conclusion Since Marx's line lies directly behind the terminal Meibomian ducts and acini, chronic stress in this region is further invoked to explain forward migration of Marx's line and the MCJ which occurs with age and the induction of primary Meibomian gland dysfunction. Arguments are put forward to explain how this mechanism might be accentuated in dry eye and how the globe might be protected from this gradient effect in the region of the ,black line', where the tear film is segregated from the meniscus after the blink. Factors pro and con the hypothesis are discussed. [source] ADENOVIRUS-MEDIATED FKBP12.6 OVEREXPRESSION INDUCES HYPERTROPHY AND APOPTOSIS IN CULTURED NEONATAL CARDIOMYOCYTESCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 2 2009Jian Zhong SUMMARY 1Cardiac ryanodine RyR2 receptors regulate Ca2+ release from the sarcoplasmic reticulum (SR). FK506 binding protein (FKBP) 12.6 prevents aberrant SR Ca2+ leakage during diastole, thereby maintaining the integrity of RyR2 function. Previous studies have focused mainly on FKBP12.6 deficiency and so the pathophysiological consequences of FKBP12.6 overexpression remain unclear. Herein, we investigate the effect of FKBP12.6 overexpression on cardiac hypertrophic and apoptotic signalling. 2Human FKBP12.6 cDNA was cloned into pAdTrack-CMV and the resulting plasmid, along with a control empty plasmid, were transfected into bacteria. The resulting virus, namely Ad-FKBP12.6 containing green fluorescent protein, was propagated and purified. Neonatal rat cardiomyocytes were infected with this virus. Protein and DNA synthesis were measured by [3H]-leucine and [3H]-thymidine incorporation, respectively. Expression of p38 mitogen-activated protein kinase (MAPK), phosphorylated extracellular signal-regulated kinase 1 or 2 (p-ERK1/2) and Bax were examined by western blotting. 3Compared with control cells, cardiomyocytes that overexpressed FKBP12.6 became hypertrophic and hyperplastic, with increased levels of both p38 MAPK and p-ERK1/2. At the same time, overexpression of FKBP12.6 induced apoptosis of cardiomyocytes, as determined by both Bax protein expression and DNA fragmentation. Rapamycin treatment downregulated the expression of p-ERK1/2, p38 MAPK and Bax in stimulated cardiomyocytes, with or without FKBP12.6 overexpression, and enhanced protein synthesis, but had no effect on DNA synthesis in cardiomyocytes. 4In conclusion, FKBP12.6 overexpression may participate in pathophysiological processes through both hypertrophic and apoptotic signalling pathways, leading to cardiomyocyte damage and death. [source] | ||||||||||